Berberine Improves Inflammatory Responses of Diabetes Mellitus in Zucker Diabetic Fatty Rats and Insulin-Resistant HepG2 Cells through the PPM1B Pathway

Abstract

Berberine (BBR), a natural compound extracted from a Chinese herb, has been shown to effectively attenuate insulin resistance (IR) and inflammation in the clinic. However, its ameliorative mechanism against IR is not well defined. This study is aimed at investigating the effect of BBR and protein phosphatase, Mg2+/Mn2+-dependent 1B (PPM1B) on IR. Biochemical measurements and liver histopathology were detected using the biochemical analyzer and HE staining in ZDF rats, respectively. Microarray analysis of liver tissues was performed, and differentially expressed gene (DEG) levels were examined by quantitative real-time PCR (qPCR) and Western blot. Additionally, the effect of BBR was also explored in HepG2-IR cells. The glucose oxidase method and the fluorescent glucose analog were used to detect glucose consumption and uptake, respectively. The PKA inhibitor H89, ELISA, qPCR, Western blot, and immunofluorescence staining were employed to estimate the expression levels of related signaling pathways. To evaluate the roles of PPM1B, HepG2-IR cells were stably infected with lentivirus targeting PPM1B. The administration of BBR drastically decreased the body weight, urine volume, blood glucose, blood urea nitrogen (BUN), CHOL, hepatic index levels, and pathologic changes and improved ALB levels in ZDF rats with PPM1B upregulation. Furthermore, BBR effectively improves glucose consumption, uptake, and inflammation in HepG2-IR cells. The knockdown of PPM1B expression aggravated the inflammatory response and glycometabolism disorder in HepG2-IR cells. Mechanistically, a reversal in the expression of cAMP, PKA, PPM1B, PPARγ, LRP1, GLUT4, NF-κB p65, JNK, pIKKβ Ser181, IKKβ, IRS-1 Ser307, IRS-1, IRS-2 Ser731, IRS-2, PI3K p85, and AKT Ser473 contributes to ameliorate IR in HepG2-IR cells with BBR treatment. Altogether, these results suggest that BBR might regulate IR progression through the regulation of the cAMP, PKA, PPM1B, PPARγ, LRP1, GLUT4, NF-κB p65, JNK, pIKKβ Ser181, IKKβ, IRS-1 Ser307, IRS-1, IRS-2 Ser731, IRS-2, PI3K p85, and AKT Ser473 expression in the liver.

Effect of Huang-Lian Jie-Du Decoction on Glucose and Lipid Metabolism in Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis

“…The main active ingredients in this formula, which were measured by HPLC, include geniposide, berberine, palmatine, etc ( YANG et al, 2019 ). These ingredients were found to be effective in treating T2DM through a variety of mechanisms ( Gu et al, 2010 ; Zhang et al, 2010 ; Li et al, 2019a ; Li et al, 2019b ; Mi et al, 2019 ; Sun et al, 2020a ; Sun et al, 2020b ; Wu et al, 2020 ). A series of clinical studies have been carried out on the treatment of T2DM with HLJDD, and promising results have been obtained.…”

Bioinformatics analysis of potential key genes and mechanisms in type 2 diabetes mellitus

“…Neutrophil degranulation [52], innate immune system [53], platelet degranulation [54], extracellular matrix organization [55], diseases of glycosylation [56], platelet activation, signaling and aggregation [57], hemostasis [58], secretion [59], secretory vesicle [60], transmembrane transporter activity [61], cell adhesion [62], localization of cell [63], extracellular matrix [55], intrinsic component of plasma membrane [64], structural molecule activity [65], signaling receptor binding [66], have been highly noted in T2DM. Reports indicate that HIF1A [67], HLA-DRB1 [68], CHI3L1 [69], ADORA2A [70], ADRB2 [71], CLU (clusterin) [72], AGT (angiotensinogen) [73], VCAM1 [74], PPARA (peroxisome proliferator activated receptor alpha) [75], APOL1 [76], ZFP36 [77], PPM1B [78], SOCS1 [79], SNCA (synuclein alpha) [80], CTSS (cathepsin S) [81], IL6R [82], CFB (complement factor B) [83], DEFB1 [84], VNN1 [85], RAB27A [86], DPP4 [87], RARRES2 [88], CASP1 [89], LCN2 [90], REG3A [91], CD74 [92], PCSK2 [93], CHGB (chromogranin B) [94], TTR (transthyretin) [95], LRG1 [96], ALB (albumin) [97], DPP7 [98], APOH (apolipoprotein H) [99], CTSD (cathepsin D) [100], GCG (glucagon) [101], KCNQ1 [102], NR4A1 [103], PLIN5 [104], ALDH2 [105], ANG (angiogenin) [106], CLDN7 [107], PRLR (prolactin receptor) [108], SOD2 [109], MLXIPL (MLX interacting protein like) [110], CTSD (cathepsin D) [111], PECAM1 [112], ADA (adenosine deaminase) [113], MFGE8 [114], COL1A1 [115], COL3A1 [116], NID2 [117], ARG1 [118], CD93 [119], IGF2 […”

Pharmacokinetics and Pharmacological Activities of Berberine in Diabetes Mellitus Treatment

“…In addition, BBR inhibited the lipopolysaccharide (LPS)/tolllike receptor 4 (TLR4)/tumor necrosis factor-α (TNF-α) pathway, suggesting that this pathway may be one of the BBR mechanisms to lower blood glucose and moderate IR [50]. Moreover, Wu et al demonstrated that BBR may alleviate IR via regulation on the protein phosphatase, Mg 2+ / Mn 2+ -dependent 1B (PPM1B) signaling pathway, including the PPM1B/inhibitor kappa B kinaseβ (IKKβ)/nuclear factor κB (NF-κB), and PPM1B/GLUT4 pathways [51]. [73].…”